The present invention relates to an agent for ameliorating ocular circulatory disorder. More particularly, the present invention relates to an agent for ameliorating ocular circulatory disorder, comprising a specific 1,4-dihydropyridine derivative or an acid addition salt thereof as an active ingredient.
An intraocular blood circulation hereinafter to be referred to as ocular circulation) has two major pathways, one being a circulation via ciliary artery and the other being a circulation via central retinal artery. The ciliary artery is connected to the arteries of choroid, optic disc, iris, ciliary body and the like, and the blood is discharged from the eye through the vortex vein. The central retinal artery passes through optic nerve and is connected to the central retinal vein, wherein a part thereof is branched into arteriola at the optic disc and then into capillary. Of these, the circulatory disorder of ciliary artery includes normal tension glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iridocyclitis and the like. The circulatory disorder of the central retinal artery includes retinal artery occlusion, retinal vein occlusion, diabetic retinopathy, ischemic optic neuropathy, choroidal disease following retinal lesion, retinochoroidal disease associated with systemic disease and the like. As is evident from the description of the above-mentioned ocular circulation pathway, the diseases caused by the above-mentioned ocular circulation disorders make an onset when the smooth circulation of retina, optic disc, choroid, iris, diary body and the like is prevented.
In recent years, there has been a high incidence of glaucoma, in particular, normal tension glaucoma (also referred to as low tension glaucoma) due to blood circulatory disorder in optic disc, and therapeutic method of the disease has been desired. By the epidemiological studies in recent years, normal tension glaucoma has been elucidated to be of a disease type of glaucoma having the highest incidence, though the intraocular pressure is in the normal range, so that it is considered to be distinct from the generally known glaucoma, namely the glaucoma caused by a high intraocular pressure. The normal tension glaucoma is generally considered to be a disease associated with (1) an intraocular pressure including a biological rhythm of not more than 21 mmHg, (2) a normal open angle, (3) glaucomatous optic disc cupping and the corresponding visual field disorder, (4) no intracranial lesion or paranasal sinuses disease which can cause optic atrophy and (5) no mass hemorrhage or shock [Low Tension Glaucoma and endotheline (ET-1), Folia Ophthalmolgica Japonica, vol. 43, pp. 554-559 (1992) and Low Tension Glaucomaxe2x80x94History and Concept, Journal of the Eye, vol. 8, pp. 493-500 (1991)).
A recent report has documented that an oral administration of a circulation ameliorating agent to a patient with normal tension glaucoma resulted in an increased optic disc blood flow and an ameliorated normal tension glaucoma [Influence of Ca2+ antagonist on changes in visual field in low tension glaucoma, Journal of Japanese Ophthalmological Society, vol. 92, pp. 792-797 (1988)]. There is a possibility that various biological vasocontracting substances that decrease blood flow may be involved in patients with normal tension glaucoma, and a significantly higher endotheline-1 (hereinafter sometimes referred to as ET-1) concentration in blood as compared to the level in healthy subjects has been reported [(Low Tension Glaucoma and Endotheline (ET-1), Folia Ophthalmolgica Japonica, vol. 43, pp. 554-559 (1992)]. ET-1 is considered to act on a receptor present in vascular smooth muscle cells and directly opens the voltage-dependent Ca2+ channel [intracellular Signal Transduction Pathway Relating to the Action and Regulation of Release of Endotheline, Experimental Medicine, vol. 8, pp. 28-35 (1990)].
Moreover, a decrease in optic disc blood flow by an injection of ET-1 into the vitreous body has been disclosed [Effect of Endotheline-1 on Ocular Circulation, Journal of Japanese Ophthalmological Society, vol. 97, pp. 678-682 (1993)]. A visual evoked potential (hereinafter also referred to as VEP) detects visual optic response of optic pathway from retinal ganglion cell to light, and can be one indication of visual field disorder. VEP shows attenuation of amplitude, disappearance of wave factor and prolonged peak latency due to disorders in retinal center and visual pathway. It has been disclosed that an injection of ET-1 results in attenuation of amplitude and prolonged peak latency [Changes in Visual Function by Injection into Endotheline Vitreous Body, Journal of Japanese Ophthalmological Society, vol. 97, pp. 467-473 (1993)]. From these, a possible involvement of various biological vasocontracting substances is suggested with respect to circulatory disorders in normal tension glaucoma, of which ET-1 is particularly plausible, wherein the possibility is suggested that ET-1 may cause an ocular circulation disorder, decrease optic disc blood flow and deteriorate visual function. Therefore, amelioration of an ocular circulation disorder induced by ET-1 is considered to be one of the effective therapeutic methods of normal tension glaucoma.
The ocular circulation disorder is most frequently seen among the retinochoroidal diseases. The retinochoroidal disease caused by an ocular circulation disorder is exemplified by retinal artery occlusion, retinal vein occlusion, diabetic retinopathy, retinitis pigmentosa, macular degeneration, choroidal disease following retinal lesion, retinochoroidal disease associated with systemic disease, and the lie. While the etiology of retinal artery occlusion and retinal vein occlusion is unknown, the lumen of retinal artery or vein is occluded to cause circulation disorder in retina and optic disc. In addition, the high ET-1 concentration in blood of a patient has been also reported [Deviation of Vasospasm Factor in Retinal Artery Occlusion, Japanese Journal of Clinical Ophthalmology, vol. 46, pp. 431-434 (1992)]. It is a well-known fact that thrombosis occurs in retinal blood vessel in diabetic retinopathy, which in turn causes retinal circulatory disorder. The retinitis pigmentosa is a binocular retinal disease, which starts with night blindness in school age, gradually progresses into abnormal visual field and visual loss, and may ultimately end in blindness. This disease is hereditary and the degeneration of retinal photoreceptor cell proceeds with increasingly narrower retinochoroidal blood vessel and circulatory disorders. An ocular circulation disorder is said to be observed in macular degeneration as well. The above-mentioned diseases that accompany ocular circulation disorder have been treated by an oral administration of tocopherol nicotinate (Juvela N : vitamin E preparation manufactured by EISAI CO., LTD.)
The optic nerve disease associated with an optic nerve disorder is exemplified by ischemic optic neuropathy and the like. The ischemic optic neuropathy gives an onset by circulatory disorder of optic nerve nutrient blood vessel. The disease accompanied by iris ciliary body circulatory disorder is exemplified by iridocyclitis and the like.
As the drug having peripheral vasodilating action, calcium antagonists representatively including nicardipine are known, which inhibit influx of Ca ion necessary for contraction of cardiac muscle and vascular smooth muscle, thereby relaxing the cardiac muscle and vascular smooth muscle and thus leading to vasodilation that increases the blood flow.
Japanese Patent Unexamined Publication No. 63-225355 discloses that certain 1,4-dihydropyridine derivative shows calcium antagonism, such as coronary arterial vasodilating action, cerebral vasodilating action, peripheral vasodilating action, intraocular smooth muscle relaxing action, renal vasodilating action and the like, thereby suggesting the usefulness thereof as a peripheral circulation ameliorating agent and for the prophylaxis and treatment of glaucoma
However, Japanese Patent Unexamined Publication No. 63-225355 fails to disclose or suggest that the peripheral vasodilating action is expressed on retinochoroid and that the intraocular smooth muscle relaxing action is expressed on retinochoroid. It also fails to refer to the inhibition of contraction of blood vessel and decrease in blood flow, or suppression of attenuation of the amplitude of VEP by ET-1. Moreover, this reference does not disclose that this derivative is useful for the prophylaxis and treatment of the diseases caused by ocular circulation disorder such as glaucoma, particularly, normal tension glaucoma, and retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, retinal vein occlusion, diabetic retinopathy, choroidal disease following retinal lesion, retinochoroidal disease accompanied by systemic disease and the like.
It has been also reported that the above-mentioned 1,4-dihydropyridine derivative increases blood flow in the brain, brown adipose tissue, small intestine, large intestine and skin of rat, but decreases blood flow in the liver, spleen, kidney, adrenal gland and skeletal muscle; that the decrease in blood flow by ET-1 can be suppressed in the kidney, adrenal gland, brown adipose tissue, small intestine, large intestine and skeletal muscle, but otherwise in the brain, lung and skin; and that the vasocontraction by ET-1 can be suppressed in the kidney, adrenal gland, brown adipose tissue, small intestine, large intestine and skeletal muscle but otherwise in the brain, lung and skin [Hypertens Res 17, 29-34 (1994)]. Therefore, while the above-mentioned blood flow increasing action of 1,4-dihydropyridine derivative and inhibition of the decrease in blood flow and vasocontraction by ET-1 are organ specific, there is no knowing if such action can be also found in retinochoroid.
The present invention aims at solving the above-mentioned problems and has been made with the purpose of providing an agent for ameliorating an ocular circulatory disorder, which has a superior blood flow increasing action in retinochoroid and which has an inhibitory action on the vasocontraction, decrease in blood flow and attenuation of the amplitude of VEP by ET-1 which is one of the biological vasocontracting substances.
The present inventors have conducted intensive studies in an attempt to achieve the above-mentioned objects and found that, from among the calcium antagonists, the above-mentioned 1,4-dihydropyridine derivative alone shows a superior blood flow increasing action in retinochoroid and an inhibitory action on vasocontraction, decrease in blood flow and attenuation of the amplitude of VEP by ET-1, and that, particularly in the form of an eye drop, the compound of the present invention does not increase intraocular pressure, though other 1,4-dihydropyridine derivatives reportedly do [nicardipine chloride (Effects of Ca2+ Channel Blocker on Intraocular Pressure and Kinetics of Aqueous Humor of House Rabbits, Journal of Japanese Ophthalmological Society, 97, 665-671 (1993)].
Accordingly, the present invention provides the following.
(1) An agent for ameliorating an ocular circulatory disorder, comprising a 1,4-dihydropyridine derivative of the formula (I) 
xe2x80x83wherein
X1 and X2 are the same or different and each is hydrogen atom, fluoromethyl, fluoromethoxy, halogen, cyano or nitro;
R1 is lower alkyl;
R2 is acyl, alkoxycarbonyl, acylalkyl, N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, nitratoalkyl, cyanoalkyl, heterocyclic alkyl, haloalkyl, alkenyl or alkynyl;
A is alkylene having a carbon atom bonded with two alkyl and having a total number of carbon atoms of 5 or more; and
m is an integer of 1 to 3,
or an add addition salt as an active ingredient.
(2) The agent for ameliorating ocular circulatory disorder of (1) above, wherein, in the formula (I), R2 is acylalkyl, N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, cyanoalkyl, heterocyclic alkyl, haloalkyl, alkenyl or alkynyl.
(3) The agent for ameliorating ocular circulatory disorder of (1) above, wherein, in the formula (I), R2 is alkenyl or alkynyl.
(4) The agent for ameliorating ocular circulatory disorder of (1) above, wherein, in the formula (I), A is alkylene having a carbon atom bonded with two alkyl and having a total number of carbon atoms of 5 to 10.
(5) The agent for ameliorating ocular circulatory disorder of any of (1) to (4) above, further comprising a compound capable of decreasing the intraocular pressure.
(6) The agent for ameliorating ocular circulatory disorder of any of (1) to (5) above, which is in the form of an eye drop.
(7) The agent for ameliorating ocular circulatory disorder of any of (1) to (5) above, which is in the form of an eye ointment.
(8) The agent for ameliorating ocular circulatory disorder of any of (1) to (7) above, which is an agent for the prophylaxis and treatment of a disease caused by a circulatory disorder in the ciliary artery system.
(9) The agent for ameliorating ocular circulatory disorder of (8) above, wherein the disease caused by the circulatory disorder in the ciliary artery system is a disease selected from the group consisting of normal tension glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy and iridocyclitis.
(10) The agent for ameliorating ocular circulatory disorder of any of (1) to (7) above, which is an agent for the prophylaxis and treatment of a disease caused by a circulatory disorder of the central retinal artery system.
(11) The agent for ameliorating ocular circulatory disorder of (10) above, wherein the disease caused by the circulatory disorder in the central retinal artery system is a disease selected from the group consisting of retina artery occlusion, retinal vein occlusion, diabetic retinopathy, ischemic optic neuropathy, choroidal disease following retinal lesion and retinochoroidal disease accompanied by systemic disease.
(12) A method for ameliorating an ocular circulatory disease, comprising administering a compound the formula (I) 
xe2x80x83wherein
X1 and X2 are the same or different and each is hydrogen atom, fluoromethyl, fluoromethoxy, halogen, cyano or nitro;
R1 is lower alkyl;
R2 is acyl, alkoxycarbonyl, acylalkyl N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, nitratoalkyl, cyanoalkyl, heterocyclic alkyl haloalkyl, alkenyl or alkynyl;
A is alkylene having a carbon atom bonded with two alkyl and having a total number of carbon atoms of 5 or more; and
m is an integer of 1 to 3,
or an acid addition salt, in an amount effective for ameliorating the ocular circulation disorder.
(13) The method for ameliorating the ocular circulation disorder of (12) above, wherein, in the formula (I), R2 is acylalkyl, N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, cyanoalkyl, heterocyclic alkyl, haloalkyl, alkenyl or alkynyl
(14) The method for ameliorating the ocular circulation disorder of (12) above, wherein, in the formula (I), R2 is alkenyl or alkynyl.
(15) The method for ameliorating the ocular circulation disorder of (12) above, wherein, in the formula (I), A is alkylene having a carbon atom bonded with two alkyl and having a total number of carbon atoms of 5 to 10.
(16) The method for ameliorating the ocular circulation disorder of any of (12) to (15) above, wherein the compound capable of deceasing the intraocular pressure is concurrently administered.
(17) The method for ameliorating the ocular circulation disorder of any of (12) to (16) above, wherein the 1,4-dihydropyridine derivative or an acid addition salt is administered in the form of an eye drop.
(18) The method for ameliorating the ocular circulation disorder of any of (12) to (16) above, wherein the 1,4-dihydropyridine derivative or an acid addition salt is administered in the form of an eye ointment.
(19) The method for ameliorating the ocular circulation disorder of any of (12) to (18) above, which is a method for the prophylaxis and treatment of a disease caused by a circulatory disorder in the ciliary artery system.
(20) The method for ameliorating the ocular circulation disorder of (19) above, wherein the disease caused by the circulatory disorder in the diary artery system is a disease selected from the group consisting of normal tension glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy and iridocyclitis.
(21) The method for ameliorating the ocular circulation disorder of any of (12) to (18) above, which is a method for the prophylaxis and treatment of a disease caused by a circulatory disorder of the central retinal artery system.
(22) The method for ameliorating the ocular circulation disorder of (21) above, wherein the disease caused by the circulatory disorder in the central retinal artery system is a disease selected from the group consisting of retinal artery occlusion, retinal vein occlusion, diabetic retinopathy, ischemic optic neuropathy, choroidal disease following retinal lesion and retinochoroidal disease accompanied by systemic disease.
(23) Use of a 1,4-dihydropyridine derivative of the formula (I) 
xe2x80x83wherein
X1 and X2 are the same or different and each is hydrogen atom, fluoromethyl, fluoromethoxy, halogen, cyano or nitro;
R1 is lower alkyl;
R2 is acyl, alkoxycarbonyl, acylalkyl, N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, nitratoalkyl, cyanoalkyl heterocyclic alkyl, haloalkyl, alkenyl or alkynyl;
A is alkylene having a carbon atom bonded with two alkyl and having a total number of carbon atoms of 5 or more; and
m is an integer of 1 to 3,
or an acid addition salt for the production of an agent for ameliorating an ocular circulatory disorder.
(24) The use of (23) above, wherein, in the formula (I), R2 is acylalkyl, N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, cyanoalkyl, heterocyclic alkyl, haloalkyl, alkenyl or alkynyl.
(25) The use of (23) above, wherein, in the formula (I), R2 is alkenyl or alkynyl.
(26) The use of (23) above, wherein, in the formula (I), A is alkylene having a carbon atom bonded with two alkyl and having a total number of carbon atoms of 5 to 10.
(27) The use of any of (23) to (26) above, wherein the agent for ameliorating the ocular circulation disorder further comprises a compound capable of decreasing the intraocular pressure.
(28) The use of any of (23) to (27) above, wherein the agent for ameliorating the ocular circulation disorder is in the form of an eye drop.
(29) The use of any of (23) to (27) above, wherein the agent for ameliorating the ocular circulation disorder is in the form of an eye ointment.
(30) The use of any of (23) to (29) above, wherein the agent for ameliorating the ocular circulation disorder is an agent for the prophylaxis and treatment of a disease caused by a circulatory disorder in the ciliary artery system.
(31) The use of (30) above, wherein the disease caused by the circulatory disorder in the ciliary artery system is a disease selected from the group consisting of normal tension glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy and iridocyclitis.
(32) The use of any of (23) to (29) above, wherein the agent for ameliorating the ocular circulation disorder is an agent for the prophylaxis and treatment of a disease caused by a circulatory disorder of central retinal artery system.
(33) The use of (32) above, wherein the disease caused by the circulatory disorder in the central retinal artery system is a disease selected from the group consisting of retinal artery occlusion, retinal vein occlusion, diabetic retinopathy, ischemic optic neuropathy, choroidal disease following retinal lesion and retinochoroidal disease accompanied by systemic disease.